Characterizations of distinct amyloidogenic conformations of the Aβ (1–40) and (1–42) peptides

Lim, Kwang Hun; Collver, Hilary H.; Le, Yen T.H.; Nagchowdhuri, Partha S.; Kenney, John M.

doi:10.1016/j.bbrc.2006.12.043

Cited by 80 publications

(92 citation statements)

References 33 publications

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“…In agreement with previous experimental and theoretical studies, 15,[17][18][19]43 we detect that the β-sheet abundance in the C-terminal region of the wild-type Aβ42 is larger than that in the structures of the wild-type Aβ40 peptide. Surprisingly, we find that this trend is different in the structures of the E22Δ mutant-type Aβ40 and Aβ42 alloforms; the β-sheet abundance is larger in the C-terminal region of the E22Δ mutant-type Aβ40 rather than in its wild-type form.…”

Section: Acs Chemical Neurosciencesupporting

confidence: 92%

“…Overall, the calculated secondary structure properties for the wild-type alloforms, for which experimental and theoretical data exist, are in excellent agreement with previously performed studies. [15][16][17][18]40,41 Figure 2 presents the free energy values for secondary structure transitions between two different secondary structure components per residue based on our free energy calculation method (see the Methods and Supporting Information for further details). Using these figures, we can identify which secondary structure component is most likely to result in the formation of a specific secondary structure of interest.…”

Section: Acs Chemical Neurosciencementioning

confidence: 99%

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The Structures of the E22Δ Mutant-Type Amyloid-β Alloforms and the Impact of E22Δ Mutation on the Structures of the Wild-Type Amyloid-β Alloforms

Coskuner

Wise-Scira

Perry

et al. 2012

ACS Chem. Neurosci.

117

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Structural differences between the intrinsically disordered fibrillogenic wild-type Aβ40 and Aβ42 peptides are linked to Alzheimer's disease. Recently, the E22Δ genetic missense mutation was detected in patients exhibiting Alzheimer's-disease type dementia. However, detailed knowledge about the E22Δ mutant-type Aβ40 and Aβ42 alloform structures as well as the differences from the wild-type Aβ40 and Aβ42 alloform structures is currently lacking. In this study, we present the structures of the E22Δ mutant-type Aβ40 and Aβ42 alloforms as well as the impact of E22Δ mutation on the wild-type Aβ40 and Aβ42 alloform structures. For this purpose, we performed extensive microsecond-time scale parallel tempering molecular dynamics simulations coupled with thermodynamic calculations. For studying the residual secondary structure component transition stabilities, we developed and applied a new theoretical strategy in our studies. We find that the E22Δ mutant-type Aβ40 might have a higher tendency toward aggregation due to more abundant β-sheet formation in the C-terminal region in comparison to the E22Δ mutant-type Aβ42 peptide. More abundant α-helix is formed in the mid-domain regions of the E22Δ mutant-type Aβ alloforms rather than in their wild-type forms. The turn structure at Ala21-Ala30 of the wild-type Aβ, which has been linked to the aggregation process, is less abundant upon E22Δ mutation of both Aβ alloforms. Intramolecular interactions between the N-terminal and central hydrophobic core (CHC), N-and C-terminal, and CHC and C-terminal regions are less abundant or disappear in the E22Δ mutant-type Aβ alloform structures. The thermodynamic trends indicate that the wild-type Aβ42 tends to aggregate more than the wild-type Aβ40 peptide, which is in agreement with experiments. However, this trend is vice versa for the E22Δ mutant-type alloforms. The structural properties of the E22Δ mutant-type Aβ40 and Aβ42 peptides reported herein may prove useful for the development of new drugs to block the formation of toxic E22Δ mutant-type oligomers by either stabilizing helical or destabilizing β-sheet structure in the C-terminal region of these two mutant alloforms.

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Section: Acs Chemical Neurosciencesupporting

confidence: 92%

Section: Acs Chemical Neurosciencementioning

confidence: 99%

The Structures of the E22Δ Mutant-Type Amyloid-β Alloforms and the Impact of E22Δ Mutation on the Structures of the Wild-Type Amyloid-β Alloforms

Coskuner

Wise-Scira

Perry

et al. 2012

ACS Chem. Neurosci.

117

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“…Zhang et al (11) used NMR to show that A␤ 10 -35 forms collapsed structures at the central hydrophobic cluster. On the other hand, other NMR studies revealed only increased structural propensities at localized short amino acid stretches (7)(8)(9)(10). Limited proteolysis studies by Lazo et al (15) show that residues 21-30 are protected in A␤40 sequence.…”

mentioning

confidence: 98%

“…The findings from these studies, however, are often found to contradict one another, probably because of different experimental conditions. A␤ in aqueous solutions has been shown to adopt a mostly random extended structure with circular dichroism spectroscopy and NMR (7)(8)(9)(10)(11)(12)(13)(14). Zhang et al (11) used NMR to show that A␤ 10 -35 forms collapsed structures at the central hydrophobic cluster.…”

mentioning

confidence: 99%

Solid-support Electron Paramagnetic Resonance (EPR) Studies of Aβ40 Monomers Reveal a Structured State with Three Ordered Segments

Ngo

Guo

2012

Journal of Biological Chemistry

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Background: A␤ monomer is the building block of neurotoxic oligomers in Alzheimer disease. Results: EPR studies of A␤40 monomers tethered on solid support show lower spin label mobility at residues 14 -18, 29 -30, and 38 -40. Conclusion: A␤40 monomer adopts a structured state with three ordered segments at 14 -18, 29 -30, and 38 -40. Significance: Structural information of A␤40 monomer is crucial for understanding the mechanism of A␤ oligomerization.

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“…Сравнительные исследования Аb40 и Аb42 в системах in vitro и in vivo показали, что Аb 42 гораздо быстрее агрегирует и обладает более высокой нейротоксичностью, чем Аb 40 [42][43][44][45][46]. Предполагается, что более высокая [47][48][49].…”

Section: ангиотензин превращающий фермент и болезнь альцгеймераunclassified

Angiotensin converting enzyme and Alzheimer's disease

Кугаевская

2013

BIOMED KHIM

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Болезнь Альцгеймера (БА) -неизлечимое дегенеративное заболевание центральной нервной системы, приводящее к деменции. В основе БА лежит нейродегенеративный процесс, приводящий к гибели нейронов коры головного мозга, связанный с образованием в мозге нейрофибриллярных клубков и отложением сенильных или амилоидных бляшек, главным компонентом которых является пептид бета-амилоид (Аb). Факторами риска развития БА являются возраст, а также гипертензия, атеросклероз, диабет и гиперхолестеринемия, в патогенез которых вовлечен ангиотензин превращающий фермент (АПФ), ключевой фермент ренин-ангиотензиновой (РАС) и калликреин-кининовой (ККС) систем. Недавно было обнаружено, что АПФ, наряду с другими металлопротеиназами, принимает участие в метаболизме Аb, расщепляя связи на N-концевом и С-концевом участках молекулы Аb. Интерес к роли АПФ в процессах деградации Аb связан с тем, что назначение ингибиторов АПФ (иАПФ) является основным терапевтическим подходом, применяемым при лечении различных форм гипертонии и других сердечно-сосудистых заболеваний. Однако до сих пор не решен вопрос о том, могут ли применяться антигипертензивные препараты, тормозящие РАС, для лечения или предупреждения БА. В настоящее время проводятся многочисленные исследования, посвященные поиску взаимосвязи между РАС и БА.Ключевые слова: болезнь Альцгеймера, пептид бета-амилоид, ангиотензин превращающий фермент, ингибиторы ангиотензин превращающего фермента.ВВЕДЕНИЕ. Болезнь Альцгеймера (БА) -один из наиболее распространенных случаев деменции, составляющий 50-60% от общего числа заболевших. Основным фактором риска развития БА является возраст. Число заболевших существенно растет после 65 лет и приближается к 50% среди людей, достигших 85 лет [1]. Хотя традиционно БА рассматривается 5

show abstract

Characterizations of distinct amyloidogenic conformations of the Aβ (1–40) and (1–42) peptides

Cited by 80 publications

References 33 publications

The Structures of the E22Δ Mutant-Type Amyloid-β Alloforms and the Impact of E22Δ Mutation on the Structures of the Wild-Type Amyloid-β Alloforms

The Structures of the E22Δ Mutant-Type Amyloid-β Alloforms and the Impact of E22Δ Mutation on the Structures of the Wild-Type Amyloid-β Alloforms

Solid-support Electron Paramagnetic Resonance (EPR) Studies of Aβ40 Monomers Reveal a Structured State with Three Ordered Segments

Angiotensin converting enzyme and Alzheimer's disease

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